The invention relates generally to wet milling apparatus for the production of fine grade particulate substances. More specifically, the invention relates to wet milling apparatus that are suitable for the production of pharmaceutical grade substances.
It is known that the rate of dissolution and therefore the bioavailability of a particulate drug can be increased by increasing surface area, i.e., decreasing particle size. Consequently, efforts have focused on methods of manufacturing finely divided particulate pharmaceutical compositions. Wet milling techniques are recognized in the production of a wide variety of fine, particulate compositions. For example, wet milling techniques are disclosed in U.S. Pat. No. 5,882,246 issued to Inkyo; U.S. Pat. No. 5,853,132 issued to Tsuji; U.S. Pat. No. 5,797,550 issued to Woodall, et al.; U.S. Pat. No. 5,791,569 issued to Ishikawa; U.S. Pat. No. 5,718,388 issued to Czekai, et al.; U.S. Pat. No. 5,593,097 issued to Corbin; U.S. Pat. No. 5,024,387 issued to Yeh; U.S. Pat. No. 4,848,676 issued to Stehr; U.S. Pat. No. 4,784,336 issued to Lu; and U.S. Pat. No. 4,624,418 issued to Szkaradek. These media mills typically include a cylindrical vessel housing a vertically or horizontally mounted agitator shaft having shear members extending therefrom. Typically, a dispersion consisting of the product to be milled and a grinding media is introduced into the vessel. Rotating the agitator causes the media to nib and shear the product into a finer grade. Since the agitator shear members are prone to excessive wear, there is widespread teaching in the prior art that they are advantageously secured to the agitator shaft using removable fasteners.
The prior art has recognized the applicability of wet milling techniques to the production of pharmaceuticals. For example, U.S. Pat. No. 5,862,999 to Czekai et al discloses the use of polymeric milling media in the production of submicron particles of a therapeutic or diagnostic agent. The use of such milling media is disclosed as advantageous in producing therapeutic and diagnostic agents that are free from contamination, due to the resistance of the polymeric media to wear or attrition.
It is desirable for pharmaceutical grade milling apparatus to be adapted for cleaning-in-place, a term that refers to cleaning and sterilization of the apparatus without disassembly and without movement of the apparatus. Typically, the apparatus is flushed with a biocompatible detergent to remove contamination or residue.
While wet milling techniques have been recognized as applicable to pharmaceutical production applications, they have not been widely adopted because known devices have not been recognized as suitable to achieve the contamination prevention and cleaning characteristics that are required of pharmaceutical grade production equipment. For example, the agitator shear member fastening techniques of the prior art have been are characterized by exposed threads, seams or crevices in the area where the shear members are fastened to the agitator shaft. In addition, the milling chamber and fittings used to secure various features therein have not heretofore been developed with attention to reducing contamination risk and improving cleanability and therefore render the milling chamber difficult to clean and prone to contamination. Typically, for example, in prior art commercial milling apparatus, non-sanitary threaded connections are used to secure components, such as the milling chamber floor and media separator screen, within the milling chamber. These characteristics of prior art milling devices present an obstacle to achieving the cleaning and contamination prevention requirements of pharmaceutical grade production equipment. It would therefore be desirable to provide a wet milling apparatus which eliminates these disadvantages.
The benefits and advantages described above are realized by the present invention which provides a wet milling apparatus that provides improved cleanability and which reduces the risk of contamination to milled compounds. The advantages are provided by an agitator which is characterized by a smooth, seamless pharmaceutical contact surface, without crevices or seams which might accumulate contamination and which might prevent removal of contamination during cleaning.
Applicants have discovered, contrary to the teachings of the prior art, that it is possible to permanently affix the agitator shear members to the agitator shaft using seamless joints, for example, polished welds, to provide a seamless agitating surface that enhances the cleanability of the agitator. Applicants have also discovered that such an agitator configuration is economically feasible and provides desirable milling characteristics when used with polymeric milling media. The welding joints formed between the agitator shaft and the projections may be finished as smooth, seamless surfaces, with no areas, such as seams or exposed thread joints, which permit the accumulation of pharmaceutical product or contamination. The agitator may therefore be cleaned and sterilized easily and without disassembly. An exemplary agitator according to the invention, has a plurality of pegs extending from a cylindrical agitator shaft. The pegs are welded to the agitator and the welds are ground smoothly and polished so that the peg and agitator surfaces form a seamless or continuous agitating surface.
In another exemplary embodiment, the agitator shaft is provided without shear members, but with a smooth, seamless cylindrical surface. The diameter of the agitator shaft is increased to provide a narrow annular clearance between the agitator shaft and the cylindrical milling chamber wall. In combination with appropriate milling media materials and sizes, desirable milling characteristics are achieved by the interaction of the milling media with the product in the narrow annular clearance. Moreover, the smooth surface of the agitator provides improved cleaning and contamination prevention characteristics.
According to another feature of the invention, the cleanability and contamination prevention features of a milling apparatus are improved through the use of seamless joints on the interior surface of the milling chamber. In an exemplary embodiment, a milling apparatus is provided with a milling chamber with a welded construction, the welds being polished to provide a smooth, seamless interior surface on the milling chamber, thereby enhancing the cleanability of the milling chamber and reducing or eliminating areas which might harbor bacteria or other contamination.
According to yet another feature of the invention, sanitary fasteners are provided for securing the media separation screen within the milling chamber. In a preferred embodiment, a threadless, sanitary, tool-free clamping fastener is provided for securing the product outlet housing, which includes the media separation screen fastened thereto, to the milling chamber wall.
Numerous other advantages and features of the present invention will become readily apparent from the following detailed description of the invention, from the claims, and from the accompanying drawings.